Gamma hydroxybutyrate is not a GABA agonist

Feigenbaum, Jeffery J.; Howard, Sherrel G.

doi:10.1016/0301-0082(96)00029-9

Cited by 44 publications

(12 citation statements)

References 70 publications

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“…This can be characterized by binding of ethyl hemisuccinate and gap‐junction blockers, including carbenoxolone hemisuccinate and β‐GRA. The existence of GHB‐sensitive (Hechler et al, 1997; Mathivet et al, 1997; Lingenhoehl et al, 1999; Castelli et al, 2004) or GHB‐insensitive (Feigenbaum and Howard, 1996) GABA B Rs (Fig. 6) has been observed previously.…”

Section: Discussionsupporting

confidence: 64%

Metabolic GHB precursor succinate binds to γ‐hydroxybutyrate receptors: Characterization of human basal ganglia areas nucleus accumbens and globus pallidus

Molnár

Fekete

Kardos

et al. 2006

J of Neuroscience Research

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Binding of the metabolic gamma-hydroxybutyrate (GHB) precursor succinate to NCS-382-sensitive [3H]GHB-labeled sites in crude synaptosomal or purified synaptic membrane fractions prepared from the human nucleus accumbens (NA), globus pallidus (GP) and rat forebrain has been shown. This site can be characterized by binding of ethyl hemisuccinate and gap-junction blockers, including carbenoxolone hemisuccinate and beta-GRA. There was no significant binding interaction between GABAB receptor ligands (CGP 55845, (R)-baclofen) and these [3H]GHB-labeled sites. GHB, NCS-382 and succinate binding profile of [3H]GHB-labeled sites in rat forebrain, human NA or GP synaptic membranes were similar. The synaptic fraction isolated from the rat forebrain was characterized by GHB binding inhibition constants: Ki,NCS-382 = 1.2 +/- 0.2 microM, Ki,GHB = 1.6 +/- 0.3 microM and Ki,SUCCINATE = 212 +/- 66 microM. In crude membranes containing mainly extrasynaptic membranes, distinct GHB and GABAB receptor sites were found in the NA. By contrast, extrasynaptic GABAB receptor sites of rat forebrain and GP were GHB- and succinate-sensitive, respectively. The heterogeneity of GABAB sites found in native membranes indicates GABAB receptor-dependent differences in GHB action. Based on these findings, we suggest that succinate (and possibly drugs available as succinate salt derivatives) can mimic some of the actions of GHB.

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Section: Discussionsupporting

confidence: 64%

Metabolic GHB precursor succinate binds to γ‐hydroxybutyrate receptors: Characterization of human basal ganglia areas nucleus accumbens and globus pallidus

Molnár

Fekete

Kardos

et al. 2006

J of Neuroscience Research

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“…The effect of 10 mM GHB was unaffected by 1 to 4 mM NCS-382 but prevented by 1 M CGP 55845 or 200 M barium. Howard, 1996;Maitre, 1997), and GHB can alter synaptic activity with GABA B receptors blocked, an effect prevented by the putative GHB receptor antagonist NCS-382 (Berton et al, 1999;Cammalleri et al, 2002;Brancucci et al, 2004). This latter action occurs at low concentrations of GHB, whereas the modulation of postsynaptic conductances requires high (millimolar) concentrations.…”

Section: Schweitzer Et Almentioning

confidence: 99%

“…The highest levels of endogenous GHB are also found in the hippocampus, a brain region strongly implicated in memory formation and seizure activity (Rolls, 2000;McCormick and Contreras, 2001). Although GHB is closely related to GABA and can activate GABA B receptors at high doses, it seems to differ from the GABA transmitter system (Feigenbaum and Howard, 1996). GHB has been used as a tool to induce a state of absence epilepsy, and several reports have suggested that GHB plays a role in absence seizures (Bernasconi et al, 1992;Banerjee et al, 1993;Maitre, 1997).…”

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confidence: 99%

γ-Hydroxybutyrate Increases a Potassium Current and Decreases the H-Current in Hippocampal Neurons via GABA_B Receptors

Schweitzer

Roberto²,

Madamba³

et al. 2004

J Pharmacol Exp Ther

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␥-Hydroxybutyrate (GHB) is used for the treatment of alcoholism and to induce absence seizures in animals, but it has also recently emerged as a drug of abuse. In hippocampal neurons, GHB may activate its own putative receptor as well as GABA B receptors to affect synaptic transmission. We used voltage-clamp recordings of rat CA1 pyramidal neurons to characterize the postsynaptic conductances affected by GHB and to further clarify the site of GHB action. Low concentrations of GHB (0.1-1 mM) did not affect postsynaptic properties, but 10 mM GHB elicited an outward current at resting potential by augmenting an inwardly rectifying potassium current and concomitantly decreased the hyperpolarization-activated H-current (I h ). Like GHB, the selective GABA Breceptor agonist baclofen (20 M) increased a potassium current and decreased I h . In the presence of 10 mM GHB, the baclofen effects were largely occluded. The selective GABA B receptor antagonist CGP 55845 [3-N[1-(S)-(3,4-dichlorophenyl)ethyl]amino-2-(S)-hydroxypropyl-p-benzyl-phosphinic acid] blocked the effects of both GHB and baclofen, whereas the putative GHB receptor antagonist 7,8,[7]annulen-6-ylidene ethanoic acid] was ineffective. The GHB and baclofen effects were prevented in the presence of 200 M barium, indicating that GHB augments a K ϩ conductance, probably a G protein-coupled inwardly rectifying K ϩ (GIRK) current. The decrease of I h by GHB and baclofen was also prevented by barium, suggesting that the diminution of I h is secondary to GIRK augmentation. Our results indicate that high GHB levels, which can be reached during abuse or intoxication, activate only GABA B receptors and not GHB receptors at the postsynaptic level to augment an inwardly rectifying K ϩ current and decrease I h .

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“…1,2) In the last decade, GHB has become one of the most frequently-encountered drugs used for both abusive and malicious purposes, such as a club drug and date-rape drug.…”

Section: Introductionmentioning

confidence: 99%

Endogenous Level and in Vitro Production of GHB in Blood from Healthy Humans, and the Interpretation of GHB Levels Detected in Antemortem Blood Samples

Shima

Miki

Kamata

et al. 2005

JOURNAL OF HEALTH SCIENCE

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The endogenous level of γ-hydroxybutyric acid (GHB) and the in vitro production of GHB in blood from healthy humans have been investigated. The endogenous GHB concentrations in aseptically collected whole blood samples ranged from 5 to 10 ng/ml, which were far below the previously-reported "endogenous" levels . Also, the levels of in vitro GHB production during storage for 16 months at 4°C were lower than 0.4 µg/ml, which were much lower than those in postmortem samples previously reported. Based on the results of this investigation, the authors concluded that an interpretative cutoff of 1.0 µg/ml would be appropriate for differentiating exogenous from endogenous GHB, if only limited to in-life blood specimens that were collected aseptically, stored at 4°C or lower, examined within two weeks, and excludes the possibility of GHB aciduria.

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Gamma hydroxybutyrate is not a GABA agonist

Cited by 44 publications

References 70 publications

Metabolic GHB precursor succinate binds to γ‐hydroxybutyrate receptors: Characterization of human basal ganglia areas nucleus accumbens and globus pallidus

Metabolic GHB precursor succinate binds to γ‐hydroxybutyrate receptors: Characterization of human basal ganglia areas nucleus accumbens and globus pallidus

γ-Hydroxybutyrate Increases a Potassium Current and Decreases the H-Current in Hippocampal Neurons via GABA_B Receptors

Endogenous Level and in Vitro Production of GHB in Blood from Healthy Humans, and the Interpretation of GHB Levels Detected in Antemortem Blood Samples

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Gamma hydroxybutyrate is not a GABA agonist

Cited by 44 publications

References 70 publications

Metabolic GHB precursor succinate binds to γ‐hydroxybutyrate receptors: Characterization of human basal ganglia areas nucleus accumbens and globus pallidus

Metabolic GHB precursor succinate binds to γ‐hydroxybutyrate receptors: Characterization of human basal ganglia areas nucleus accumbens and globus pallidus

γ-Hydroxybutyrate Increases a Potassium Current and Decreases the H-Current in Hippocampal Neurons via GABAB Receptors

Endogenous Level and in Vitro Production of GHB in Blood from Healthy Humans, and the Interpretation of GHB Levels Detected in Antemortem Blood Samples

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γ-Hydroxybutyrate Increases a Potassium Current and Decreases the H-Current in Hippocampal Neurons via GABA_B Receptors